This document discusses treatment considerations for glomerulonephritis. It outlines several immunosuppressive medications used to treat glomerular diseases like corticosteroids, calcineurin inhibitors, alkylating agents, azathioprine, mycophenolic acid, rituximab, and eculizumab. Each medication is described in terms of its mechanism of action, major adverse effects, and strategies to reduce toxicity. The document also notes that treatment decisions require weighing a patient's risk of progression, comorbidities, and plans for childbearing against the risks of medication side effects.

1. TREATMENT OF
GLOMERULNEPHRITIS
Christine Victoria C, Aldaba
Year I Fellow
East Avenue Medical Center
Section of Nephrology

2. Three primary areas for consideration when evaluating a treatment plan
for an individual patient.
1. Specific disease-associated risks and treatment goals
2. Patient characteristics
3. Specific medication toxicities

3. PROTEINURIA has different implications dependent upon the
underlying diagnosis
Rate of renal function decline according to sustained proteinuria varies
according to histologic diagnosis
Proteinuria reduction  crucial element in balancing the risks and
benefits of treatment, surrogate endpoint for renal survival

5. Associated with a poor outcome:
1. Severity of initial proteinuria and renal function at presentation
2. Extent of tubulointerstitial disease on histologic examination
Best predictor of renal survival – COMPLETE remission of proteinuria
FOCAL AND SEGMENTAL
GLOMERULOSCLEROSIS

6. • Proteinuria - tightly correlated with renal outcome in patients with IgAN
• Association between proteinuria reduction and both improved renal survival and
prolonged time to doubling of serum creatinine
• Other modifiable factors identified: Mean arterial pressure and exposure to renin–
angiotensin system blockade, but level of sustained proteinuria was the
dominant modifiable risk.
IGA NEPHROPATHY

7. • Should be well understood by patients and clinicians at the start of therapy to avoid
excessive exposure to toxicities and premature escalation or interruption of
treatment.
• Membranous Glomerulopathy : earliest signs of response is evident at 3 months.
• Full response to treatment can take 12 months.
TIMING OF RESPONSE

8. 1. Corticosteroids
2. Calcineurin Inhibitors
3. Alkylating Agents
4. Azathioprine
5. Mycophenolic Acid
6. Rituximab
7. Eculizumab
TREATMENT OF
GLOMERULNEPHRITIS

9. Most common anti-inflammatory and immunosuppressive drugs used in the
treatment of both primary and secondary GN
Mechanism of Action:
Reversible blocking of T-cell and antigen-presenting cell–derived cytokine
and cytokine-receptor expression
Anti-inflammatory activity:
Inhibition of synthesis of proinflammatory cytokines such as interleukin-2, -6, -8
and tumor necrosis factor  glomerular and tubulointerstitial injury
CORTICOSTEROIDS

10. Infection  COMMON RISK to all immunosuppressant medications
WIDESPREAD SYSTEMIC SIDE EFFECTS:
 Impaired glucose tolerance
 Cardiovascular and GIT toxicity
 Severe musculoskeletal damage
 Cosmetic, ophthalmological and psychiatric effects
MAJOR ADVERSE EFFECTS

11. Glucose metabolism e metabolism
Increased doses of GCs  ↑ risk of hyperglycemia
Musculoskeletal – proximal weakness, atrophy, myalgia
STEROID MYOPATHY – exposure to fluorinated steroids
(i.e. Dexamethasone, Betamethasone, Triamcinolone)
MANAGEMENT: Discontinuation of steroid
↑ hepatic gluconeogenesis
↓ peripheral tissue insulin sensitivity
CORTICOSTEROIDS

12. • ↑ risk of bone fracture – 2.5 to 7.5mg/day
• Avascular necrosis - devastating destruction of the head of
the femur or other long bones; less clear relationship with dose
of prednisone
• Vision – cataract formation and increased intraocular pressure
• Impaired wound healing, GI effects (gastritis and bleeding)
• Mood lability and insomnia – contribute to poor patient
tolerance
CORTICOSTEROIDS

13. • CARDIOTOXCIITY TOXICITY
• CARDIOVASCULAR EVENTS result after dose adjustment
for traditional risk factors (ie. Hypertension, glucose
intolerance and obesity)
CORTICOSTEROIDS

14. • Alternate day steroids
• Shortening the course of therapy
• More rapid tapering of prednisone
• VERY HIGH RISK: Calcineurin Inhibitor (CNI) – used as second
line therapy; or as first-line approach for those with pre-existent
obesity, history of psychosis.
STRATEGIES FOR REDUCING TOXICITY

15. • Use of antibiotics
• Regular eye examinations for those with DM
• Adjustment of antihypertensive regimen
• Proton pump inhibitor for gastric protection
• > 8-12 weeks of daily GC (0.5-1mg/kg)  add Vit D 1,000 U/day and
Calcium 1 g/day
• Addition of bisphosphonates – guided by bone density evaluation, age, patient-
specific risks, risk of teratogenicity
ALTERNATE STRATEGIES

16. Cyclosporine and Tacrolimus
Mechanism of Action:
Downregulates T-cell activation, blocks calcium-dependent T–cell receptor
signaling transduction  inhibits transcription of IL-2
Interleukin-2 - major activation factor for T cells and a key modulator of both T-
and B-cell activity in numerous immunological processes
Stabilize the internal cytoskeletal structure of the glomerular podocyte
CALCINEURIN INHIBITORS

18. Nephrotoxicity - most significant adverse effect; risk of CKD if given in higher
doses for prolonged periods
New onset or worsening of “hypertension” – contributes to its long-term
nephrotoxic potential
Impaired insulin secretion and increased insulin resistance
Induction of glucose intolerance and overt diabetes
Cosmetic - gum hypertrophy (25.4%), and hypertrichosis (less frequent with
tacrolimus than cyclosporine)
MAJOR ADVERSE EFFECTS

19. Maintain remission: Long-term low-dose therapy with cyclosporine (1.0–2
mg/kg per day) +/- low dose steroids
Lower toxicity  lower daily maintenance dose required and gradual
increase in dose to achieve therapeutic effect
Careful monitoring of drug levels, frequent monitoring of renal function
are MANDATORY
Nephrotoxicity – renal vasoconstrictive properties, concomitant intake of
renin-angiotensin system blockade AKI
STRATEGIES FOR REDUCING
TOXICITY

20. Cyclophosphamide - the most common drug
Chlorambucil – less common drug, different adverse effect profile and
drug tolerability
Mechanism of action:
Induces DNA damage by inducing apoptosis or altered function of both
B cells and T cell
ALKYLATING AGENTS

21. • Infertility in both men and women - most concerning long-term side effect
 Permanent ovarian failure - 26% if given 10-20g cyclophosphamide; >70% if >30g
 Gonadal toxicity - >300 mg/kg  reduction in sperm count
• Malignancy: Cumulative dose of >36g of cyclophosphamide (equivalent to
2 mg/kg for 8 months in a 70-kg patient)
• Bone marrow suppression (white cell line) - 25% of patients with Lupus
nephritis showed leukopenia
• Increased susceptibility to infections
• Alopecia, hemorrhagic cystitis
MAJOR ADVERSE EFFECTS

22. Chlorambucil - alternative alkylating agent used in the treatment
of membranous nephropathy.
Adverse effects:
- Similar to Cyclophosphamide
- Not associated with bladder toxicity and gross hematuria
- Less well tolerated overall
- Risk of acute myelogenous leukemia
MAJOR ADVERSE EFFECTS

23. Strategies to limit exposure focus on limiting duration of
therapy rather than modifying the dose.
IV Cyclophosphamide in Lupus and Vasculitis – less frequent and
smaller doses are effective with fewer adverse events.
Membranous Nephropathy – shorter-duration regimen of exposure is
considered an option (exposure is limited to 3 months)
Substitution with Mycophenolate mofetil (MPA) or
Azathioprine for maintenance therapy in lupus nephritis
STRATEGIES FOR REDUCING
TOXICITY

24. Replacement with CNIs – treatment failed, patient relapsed, or
repeated exposure to CNI is considered
 Membranous nephropathy, Lupus nephritis, or FSGS
Monitor adverse effects: Frequent blood counts, adjusting the
dose relative to degree of renal impairment, age, and other
comorbid conditions
TERATOGENIC - Contraception counseling is required for
sexually active men and women
STRATEGIES FOR REDUCING
TOXICITY

25. Azathioprine is an inhibitor of inosine monophosphate dehydrogenase,
an enzyme critical for purine synthesis  required for lymphocyte division
RESULT: ↓ levels of both B and T lymphocytes as well as immunoglobulin
synthesis
Metabolite: 6-thio-guanosine-5′-triphosphate (trio-GTP) blocks guanosine-
5′-triphosphatase activation in T lymphocytes  Immunosuppression
AZATHIOPRINE

26. • GI side effects: nausea and vomiting
• Liver toxicity: increase in serum transaminase levels
• Dose-related bone marrow suppression (white blood cells)
• Malignancies (skin cancers)
• Bacterial and viral infections
MAJOR ADVERSE EFFECTS

27. • Thiopurine methyltransferase (TPMT) is an enzyme that metabolizes a class of
drugs called thiopurines.
• Thiopurines - drugs are used to suppress the immune system and are prescribed
to treat various immune-related conditions.
• Slowly dose escalate while surveying for toxicity
• Dose reduction improves myelosuppression
• Allopurinol and febuxostat - both contraindicated when using azathioprine due to
risk of leukopenia
• Monitoring of hepatotxicity and pancreatitis
STRATEGIES FOR REDUCING
TOXICITY

28. • Available as mycophenolate mofetil
• A reversible inhibitor of inosine monophosphate dehydrogenase, an enzyme
critical for purine synthesis  required for lymphocyte division
Factors that contribute to the lymphocyte-specific effects of MPA on purine
metabolism:
1. Lymphocytes are uniquely dependent upon de novo purine synthesis to generate
RNA and DNA
2. MPA is potent inhibitor of inosine monophosphate dehydrogenase – expressed in
activated lymphocytes  contributes to specificity
REDUCED TOXICITY – selective inhibition of lymphocyte proliferation, does NOT
affect all dividing cells.
MYCOPHENOLIC ACID

29. GI symptoms : nausea, vomiting, diarrhea  more common with MPA
Hematologic: leucopenia and anemia
Infection – myelosuppression
Teratogenic
MAJOR ADVERSE EFFECTS

30. • Splitting the dosage reduces GI problems
• GI infections, leucopenia - temporary dose reduction
• If full dose is NOT tolerated, add MPA-sparing agents such as low dose steroid
or CNI
• Negative pregnancy test prior to initiating the therapy
• Contemplating pregnancy : Off MPA at least 6 weeks before conception
STRATEGIES FOR REDUCING
TOXICITY

31. Rituximab is a genetically engineered, human monoclonal antibody directed against
the CD20 antigen expressed on surface of normal and malignant pre-B and mature
B cells
SAFETY PROFILE: Not expressed on hematopoietic stem cells, pro-B cells, normal
plasma cells, or other normal tissues
Elimination of B cells - dampening effects on other immune cells such as T
lymphocytes, dendritic cells, and macrophages
RITUXIMAB

32. • Fc portion of rituximab binds human complement and can lead to cell lysis of
the targeted cell through complement-dependent cytotoxicity
• Rituximab may have a direct podocyte-modulating effect and regulation of acid
sphingomyelinase essential for the lipid-raft compartmentalization of the
podocyte plasma membrane
• This potential direct effect on podocytes make it a very effective option to
consider for the treatment of idiopathic glomerular diseases
RITUXIMAB

33. • Acute infusion-related reactions : rash, pruritus, flushing, nausea, vomiting, fatigue,
headache, flu-like symptoms, dizziness, runny nose, hypertension.
• Anaphylaxis and shock - <1%
• Others: anemia, cardiac arrhythmias, respiratory failure, and acute kidney injury
• More delayed adverse effects: reactivation of latent viral Hepatitis B infection and
several cases of pneumocystis
• Vaccination with LIVE organisms should be AVOIDED.
MAJOR ADVERSE EFFECTS

34. • Careful dose infusion escalation
• Premedication with antihistamines and corticosteroids
• The precise dose and/or regimen to use in patients with autoimmune disorders is
unknown.
STRATEGIES FOR REDUCING
TOXICITY

35. Eculizumab is an anti-C5 (complement factor 5) monoclonal antibody used in diseases
characterized by impaired inhibitors of the activation of the alternative complement
pathway
Complement dysregulation : Critical contributor to many forms of progressive
glomerular injury traditionally attributed to classical or lectin-activated complement
pathways.
Relevant in the context of C3 Nephropathy and dense deposit disease, idiopathic
immunoglobulin-mediated forms of membranoproliferative glomerulonephritis,
systemic lupus erythematosus, and other variants of GN
ECULIZUMAB

36. • Overall, eculizumab is well tolerated
• Potential for an increased risk for infection by encapsulated
bacteria such as Neisseria meningitides
MAJOR ADVERSE EFFECTS

37. • Vaccination before instituting therapy and careful surveillance are recommended
• Prophylactic antibiotics
• The precise dose and/or antibiotic regimen to use in patients with glomerular
diseases are presently unknown.
STRATEGIES FOR REDUCING
TOXICITY

38. We consider the following questions before making guideline-based treatment
recommendations:
1. What is the risk of progression to kidney failure in this
individual patient?
Proteinuria is one of our main considerations when we decide whether or not there is
an advantage to addition of immunomodulatory treatment to conservative therapy.
Renal insufficiency at presentation and progression of renal insufficiency during
observation should also be considered.
TREATMENT ALGORITHMS
AND CONSIDERATIONS

39. A common clinical error is to put patients with irreversible kidney injury at risk with
little chance of benefit.
2. What are the patient’s comorbid conditions?
Important variables to consider: Age, personal or family history
of glucose intolerance, obesity, cancer history, and prior
cumulative immunosuppression exposure.
TREATMENT ALGORITHMS
AND CONSIDERATIONS

40. 3. What are plans for childbearing?
Important considerations: Teratogenicity of drugs, the effects of the medications
on fertility, and the optimization of renal health before pregnancy.
Addition of nursing guidance and supervision, dietary counselling, pharmacy
support, as well as social supports ultimately improve both
patient safety and the disease experience of this unique population.

41. THANK YOU!